Peptides cyclization

Grunewald, J., Kopp, F., Mahlert, C., Linne, U., Sieber, S. A. and Marahiel, M. A. (2005). Fluorescence resonance energy transfer as a probe of peptide cyclization catalyzed by nonribosomal thioesterase domains. Chem. Biol. 12, 873-881. 

There have been reports that urethane was produced when the mixed-anhydride method was employed for the coupling of segments. However, studies on urethane formation during the aminolysis of mixed anhydrides of peptides have never been carried out. The anhydrides are too unstable to be isolated. The activated moiety of the peptide cyclizes too quickly to the 2,4-dialkyl-5(4//)-oxazolonc (see Section 2.23), and since the time allowed to generate the anhydride in segment couplings is always limited to avoid epimerization, one cannot exclude the possibility that the urethane that was produced originated by aminolysis of unconsumed chloroformate. 

Due to the vast numbers and rapidity of novel developments in solid-phase synthesis over the past ten years, a number of reports currently found in the literature deal with solid-phase syntheses of lanthionine peptides. There are at least two different approaches to synthesize lanthionine peptides in which the sulfide bond links amino acid halves that are not direct neighbors within the peptide chain (Scheme 10). One obvious approach, method A, is based on the coupling of a preformed, orthogonally protected lanthionine monomer to the N-terminus of a peptide oxime resin. 48 This is then followed by acid-catalyzed cyclization and simultaneous release from the resin during amide bond formation with the C-terminal carboxy group via the peptide cyclization method on oxime resin (see Section 6.73.2.2). The alternative approach is lanthionine formation after peptide synthesis from amino acid derivatives, such as serine and cysteine (method B). 

Mode of Cyclization2 Resinb (Final Deprotection) Peptide Cyclization Reagent(s) Detection Method Preferred Reagent Ref... 

Scheme 17 General Strategies for Peptide Cyclizations On Resin Involving the C-Terminal Carboxy Group...

Early work in the field has established the synthetic strategies and analytical tools for such class of libraries (for reviews see refs[111 112 456]). As listed in Table 13, the first generation of cyclic peptide libraries focused on biologically active sequences such as the cell adhesion RGD motif, the antileukemic heptapeptide stylostatin, or endothelin antagonists, but also on metal-binding sequence motifs and on the de novo discovery of bioactive cyclic peptides without sequence-biased motifs. Moreover, synthetic questions were addressed such as the sequence dependency of peptide cyclization reactions (see Table 13). 

Dithiol melanotropin peptide cyclized via rhenium metal coordination PDB ID IBOQ... 

Due to the good nucleophilic nature of sulfur, formation of new C—S bonds is relatively easy. This property has been used for intramolecular peptide cyclization 1 and was exploited for preparation of methylenethio ether surrogates, t >[CH2—S], initially as peptide gap inhibitors for blocking collagenase action. 2 These surrogates were later converted into sulfoxide and sulfone derivatives. This expansion of amide replacements compelled a more generalized nomenclature system for pseudopeptides (amides with one or more amide bond surrogates) and led directly to the psi-bracket convention. 1 ... 

Peptide cyclization significantly reduces this flexibility, as shown by model studies with cyclic pseudodipeptides. When incorporated into biologically active cyclic peptides, potencies are generally retained or even enhanced. But flexibility is still a feature since pseudopeptide analogues of the p-receptor-selective opioid parent peptide, Tyr-c[-D-Lys-Gly-Phe-Leu-], were potent but nonselective with respect to activity toward p- and 6-re-ceptorsJ50]... 

Since all naturally occurring phencyclopeptines have the same stereochemistry at C-9, a synthetic route involving peptide cyclization of the p-nitrophenyl ester (22) to give a single diastereoisomeric cyclic peptine (23) suggests a feasible route to the total synthesis of these natural products.18 Pubescine A (24), obtained from the... 

There are five commonly observed classes of cyclic peptides. The most common of these is a head-to-tail cyclic product, seen in Fig. 2, in which lactamization occurs between the carboxyl and amino termini. Alternatively, cyclization can be effected between a side chain and the carboxyl terminus or amino terminus of the peptide. Cyclization may also be achieved between two side chains, which often involves the use of an additional chemical spacer. The final method by which cyclization may be attained is through two backbone amide nitrogens. All these strategies have different requirements for the orthogonal protecting groups employed. 

Richter, L. S., Tom, J. Y. K., and Burnier, J. P. (1994) Peptide-cyclizations on sohd support—a fast and efficient route to small cyclopeptides. Tetrahedron Lett. 35, 5547-5550. 

Scheme 4 Mechanistic proposal for the photo-induced peptide cyclization...

Kohli RM, Trauger JW, Schwarzer D, Marahiel MA, Walsh CT. 25. Generality of peptide cyclization catalyzed by isolated thioesterase domains of nonribosomal peptide synthetases. Biochemistry 2001 40 7099-7108. 

It is also worthwhile to note that the relatively slow catalytic hydrogenolysis of A/ -Z-protected peptide derivatives pemnits some interesting chemical transformations to be performed in situ. For example, direct conversion of Z protection to Boc protection is possible when the hydrogenation is conducted in the presence of di-tert-butyl dicarbonate under neutral conditions.h Alternatively, the same transformation is achieved by the use of triethylsilane and di-tert-butyl dicarbonate in ethanol with catalytic amounts of palladium(II) acetate.h 1 More efficiently this one-pot transformation is achieved by catalytic transfer hydrogenation in the presence of di-terf-butyl dicarbonate (cf. Section 2.1.1.1.3.1.1.6).h l Similarly, peptide cyclization reactions have been performed in situ over Pd/C and the high yields of cyclic monomers are attributed to the high dilution effect as well as to catalysis of the charcoal surface.h l... 

More recently another modification for the preparation of peptide azides was introduced by Alfeeva et al-f l using tetrabutylammonium nitrite as auxiliary reagent. In contrast to the alkyl nitrites which are relatively unstable and therefore have to be purified prior to use by distillation, tetrabutylammonium nitrite is a crystalline and stable compound, which is soluble in anhydrous dipolar aprotic solvents. Moreover, in this procedure the acidity of the reaction mixture is adjusted with anhydrous p-toluenesulfonic acid instead of HCl in anhydrous organic solvents. These conditions are experimentally convenient and more easily controlled than those of the Honzl-Rudinger method. Comparative model reactions performed with ferf-butyl nitrite and tetrabutylammonium nitrite produced nearly identical peptide yields. To date, there are no reports of the condensation of larger fragments and peptide cyclization by this azide procedure. 

Section 3.7), uroniuno/guanidinium compounds tend to modify the annino group when used in excessf l (Section 3.8.1.2). These limitations need to be considered when uronium/ guanidinium salts are employed for peptide cyclization, especially when used under solid-phase conditions.For a detailed discussion of the synthesis of cyclic peptides in general, see Section 6.8. 

Pseudoprolines for Enhancing Peptide Cyclization and Turn Induction... 

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